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BIBLIOGRAFIA NACIONAL QUIMICA

2000

Abstract

For glutathione reductase (GR), amammalian reduced nicotinamide adenine dinucleotide phosphate dependent ¯avoenzyme participating in free-radical detoxi®cation pathways, we present a quantum chemical study addressing aspects of its electronic mechanism. The system is known to sustain both ping-pong and sequentially ordered mechanisms depending upon par- ticular conditions. Isoalloxazine and nicotinamide- N-protonated rings are taken as a minimum model. The AM1 method and the AMSOL program are used throughout. Starting from a transition-state structure, docked at GRs active site, and successively including molecular elements of the active site relevant to the redox processes, geometry-optimized binary and tertiary complexes are characterized suggesting a plausible description for the sequentially ordered mechanism. The ping-pong mechanism relates to an electron-transfer (ET) mechanism. An ET binary complex between nicotinamide and the isoalloxazine ring was character- ized. Its electronic structure is controlled by the proto- nation state of the proton relay found at this active site. The excess proton in the relay comes from the previous hydride-transfer step. The experimental stereoselectivity is then ful®lled. The state of charge (standard Mulliken population analysis) shows an excess of two electrons on the isoalloxazine ring and almost one on the nicotin- amide ring. The overall results suggest that both mechanisms can be controlled by the same hydride- transfer structure, the dierence between them being determined by changes in the oxidized coenzyme binding strength to the protein and/or the strength of the protein±substrate interactio